Targeting of anti-citrullinated protein/peptide antibodies in rheumatoid arthritis using peptides mimicking endogenously citrullinated fibrinogen antigens

Arthritis Res Ther. 2015 Jun 10;17(1):155. doi: 10.1186/s13075-015-0666-6.


Introduction: We have previously identified endogenously citrullinated peptides derived from fibrinogen in rheumatoid arthritis (RA) synovial tissues. In this study, we have investigated the auto-antigenicity of four of those citrullinated peptides, and explored their feasibility to target anti-citrullinated protein/peptide antibodies (ACPA).

Methods: The autoantigenic potential of the fibrinogen peptides was investigated by screening 927 serum samples from the Epidemiological Investigation of RA (EIRA) cohort on a peptide microarray based on the ImmunoCAP ISAC® system. In order to assay for ACPA blocking, two independent pools of purified ACPA were incubated with the respective targeting peptide prior to binding to cyclic citrullinated peptide (CCP)2 using the CCPlus® ELISA kit.

Results: Two peptides derived from the fibrinogen α chain, Arg573Cit (563-583) and Arg591Cit (580-600), referred to as Cit573 and Cit591, and two peptides from the fibrinogen β chain, Arg72Cit (62-81) and Arg74Cit (62-81) (Cit72 and Cit74), displayed 65%, 15%, 35%, and 53% of immune reactivity among CCP2-positive RA sera, respectively. In CCP2-negative RA sera, a positive reactivity was detected in 5% (Cit573), 6% (Cit591), 8% (Cit72), and 4% (Cit74). In the competition assay, Cit573 and Cit591 peptides reduced ACPA binding to CCP2 by a maximum of 84% and 63% respectively. An additive effect was observed when these peptides were combined. In contrast, Cit74 and Cit72 were less effective. Cyclization of the peptide structure containing Cit573 significantly increased the blocking efficiency.

Conclusions: Here we demonstrate extensive autoantibody reactivity against in vivo citrullinated fibrinogen epitopes, and further show the potential use of these peptides for antagonizing ACPA.

MeSH terms

  • Arthritis, Rheumatoid / immunology*
  • Autoantibodies / immunology*
  • Autoantigens / immunology*
  • Citrulline / immunology
  • Enzyme-Linked Immunosorbent Assay
  • Epitopes / immunology
  • Fibrinogen / immunology*
  • Humans
  • Peptides / immunology
  • Peptides, Cyclic / immunology*
  • Protein Array Analysis


  • Autoantibodies
  • Autoantigens
  • Epitopes
  • Peptides
  • Peptides, Cyclic
  • cyclic citrullinated peptide
  • Citrulline
  • Fibrinogen